Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Am J Obstet Gynecol. Author manuscript; available in PMC 2012 September 1.
Published in final edited form as:
PMCID: PMC3217181

Treatment of abnormal vaginal flora in early pregnancy with clindamycin for the prevention of spontaneous preterm birth: a systematic review and metaanalysis


The purpose of this study was to determine whether the administration of clindamycin to women with abnormal vaginal flora at <22 weeks of gestation reduces the risk of preterm birth and late miscarriage. We conducted a systematic review and metaanalysis of randomized controlled trials of the early administration of clindamycin to women with abnormal vaginal flora at <22 weeks of gestation. Five trials that comprised 2346 women were included. Clindamycin that was administered at <22 weeks of gestation was associated with a significantly reduced risk of preterm birth at <37 weeks of gestation and late miscarriage. There were no overall differences in the risk of preterm birth at <33 weeks of gestation, low birthweight, very low birthweight, admission to neonatal intensive care unit, stillbirth, peripartum infection, and adverse effects. Clindamycin in early pregnancy in women with abnormal vaginal flora reduces the risk of spontaneous preterm birth at <37 weeks of gestation and late miscarriage. There is evidence to justify further randomized controlled trials of clindamycin for the prevention of preterm birth. However, a deeper understanding of the vaginal microbiome, mucosal immunity, and the biology of bacterial vaginosis will be needed to inform the design of such trials.

Keywords: antibiotic, bacterial vaginosis, clindamycin, late miscarriage, preterm birth

Spontaneous preterm labor and delivery is a syndrome caused by multiple pathologic processes that activate the common pathway of parturition.1,2 Mechanisms of disease involved in the “preterm labor syndrome” include infection/inflammation,314 vascular disease,1517 uterine overdistension,1821 abnormal allograft reaction (eg, rejection),2224 an allergic-like phenomenon,2528 a progesterone deficiency,2932 and cervical disorders.3336 The first mechanism of disease responsible for preterm labor and delivery for which a causal link was well-established is infection.3,8,11,13,3739 Moreover, the mechanisms responsible for this process have been identified and involve pattern recognition receptors,4044 chemokines,4549 or inflammatory cytokines.5053

A conventional view is that most cases of intrauterine infection responsible for preterm labor and delivery result from ascending infection;3,8 therefore, multiple investigators have attempted to identify the patient at risk for preterm labor and delivery by assessing the microbiologic state of the lower genital tract.5461 Several cohort studies have attempted to establish a relationship between a change in the lower genital tract flora and the risk of preterm delivery.6272 Moreover, randomized clinical trials have been undertaken to test the effect of antibiotics in patients with bacterial vaginosis (BV),7387 Trichomonas vaginalis,88 group B streptococci (GBS),89,90 Ureaplasma urealyticum,91,92 and Chlamydia trachomatis.93

The initial expectation that assessing the lower genital tract for the presence of certain microorganisms or changes in the microbial flora (ie, BV) followed by treatment has not met initial hopes. We believe that the disappointing results are not due to any question about the importance of infection in the etiology of preterm labor and delivery (with intact or ruptured membranes), but rather the limitations of the experimental design of the randomized clinical trials implemented to test the effects of antimicrobial agents.

A fundamental principle of randomized clinical trials is that all patients included in a particular trial must potentially benefit from the intervention under study (in this case, antibiotics). Therefore, if the goal of antibiotic administration is to reduce preterm labor and delivery, this can only be accomplished by preventing infection-induced preterm labor and delivery.94,95 Consequently, randomized clinical trials designed to test hypotheses must identify patients at risk for infection, and such risks must be substantial in order for the trial to have a reasonable expectation of success.

Intraamniotic infection/inflammation can be readily identified by analysis of amniotic fluid.96 However, it would be convenient to identify these patients by examining changes in the microbial flora of the lower genital tract, because this would be relatively easy and non-invasive. BV is characterized by a change in the microbial ecosystem of the vagina.97,98 Its presence is associated with an increased risk for spontaneous preterm delivery71,97108 and intraamniotic infection.109112 Therefore, investigators reason that identification and treatment of BV would result in a decreased rate of preterm delivery. Many randomized clinical trials have been conducted to test this hypothesis, and the results have been largely negative;7381 although, some trials have yielded positive results.8287

The contradictory results among trials of BV have been attributed to: (1) the definition of BV; (2) the gestational age at diagnosis and enrollment; (3) the choice of antimicrobial agent used, as well as the dose and route of administration; (4) whether antibiotic administration has been followed by a test of cure; (5) the primary outcome of the study (most have used delivery at <37 weeks rather than early preterm delivery, where most of the infection-related preterm births [PTBs] occur);113 (6) gene-environment interactions related to the inflammatory response;114116 and (7) patient population, etc.

For antibiotics to be effective in reducing the rate of preterm delivery, several criteria must be met:95 (1) antimicrobials must be effective against the target organism or the clinical condition under study (eg, BV); (2) antimicrobials should be used only in women who can benefit because they are at substantial risk for infection or an infection-related condition; and (3) antimicrobials must be used early enough117 so that eradication of the microorganisms would be followed by resolution of any inflammatory response66,118,119 and its unintended consequences (eg, damage of the chorioamniotic membranes, microbial invasion of the amniotic cavity, fetal microbial invasion, and fetal inflammation).120122

The importance of the timing of antibiotic administration has recently become more apparent because there is evidence that exposure to either bacterial products (eg, endotoxin or lipopolysaccharide) or bacteria itself, which is not enough to signal the onset of preterm labor, may predispose to a subsequent viral infection, and this, in turn, leads to both preterm labor and fetal damage.123

Several systematic reviews and metaanalyses have been conducted to determine the effect of antimicrobial agents for the prevention of PTB in women with BV.124133 Such efforts need to be revisited to focus both on clindamycin and early treatment.86,87,134

The purpose of this study was to conduct a systematic review and metaanalysis to determine whether treatment of patients with BV with clindamycin before 22 weeks of gestation can reduce the rate of spontaneous PTB. The justification for the study is that several trials have suggested a beneficial effect of this antibiotic in reducing the rate of PTB in patients at risk when administered early during pregnancy. Most studies aimed at reducing the rate of PTB have used metronidazole, and such studies have yielded negative results.

Materials and methods

The systematic review was conducted using a prospectively prepared protocol and reported with the use of the Preferred Reporting Items for Systematic Reviews and Meta-analyses.135

Literature search

A computerized search was performed with PubMed, Embase, Cinahl, and Lilacs (all from inception of database to July 31, 2011), ISI Web of science (; 1960 to July 31, 2011), the Cochrane Central Register of Controlled Trials (; 1960 to July 31, 2011), and Research Registries of ongoing trials (,,,,, and with a combination of key and text words that are related to antibiotics, BV, prevention, or PTB. Proceedings of the Society for Maternal-Fetal Medicine and international meetings on PTB, reference lists of identified studies, textbooks, previously published systematic reviews, and review articles were also explored. No language restrictions were applied. All searches were carried out independently by 2 authors (R.F.L. and C.N.), and the results were merged. For studies that were reported in multiple publications, the data from the publication with the report of the primary outcomes and the largest sample size were used.

Study selection

We included randomized controlled trials that compared early treatment of women at <22 completed weeks of gestation with abnormal vaginal flora and asymptomatic BV that was diagnosed using objective criteria, with either oral clindamycin or clindamycin vaginal cream (CVC) vs placebo or no intervention. Only studies whose primary aim was to prevent PTB (delivery at <37 weeks of gestation) were included in the analysis. Quasirandomized studies were excluded. Other inclusion criteria consisted of pregnant women with a gestational age of <22 weeks of gestation at screening and commencement of treatment who were not in labor, had no vaginal bleeding, and did not report symptoms of lower genital tract infection. The diagnosis of BV was based on first trimester or early second trimester screening programs through the identification of abnormal lower genital tract flora and BV with the use of screening Gram stains scored by the Spiegel et al,136 Nugent et al,137 Hay et al,71 or Ison and Hay138 criteria. Studies with rescreening and retreatment protocols were included in the final analysis. All studies that were deemed appropriate were retrieved and reviewed independently by the 2 screening authors to determine inclusion. Disagreements were resolved through consensus discussions.

Outcome measures

The primary outcomes of interest were spontaneous PTB at <37 completed weeks of gestation and late miscarriage (LM; birth between 16 and 23 completed weeks of gestation). Spontaneous PTB <37 completed weeks of gestation was chosen because this primary outcome was used in most metaanalyses that evaluated preventative strategies for PTB. Secondary outcomes included birthweight, low birthweight, very low birthweight, gestational age at delivery, early PTB (<30 completed weeks of gestation), admission to the neonatal intensive care unit (NICU), success of treatment according to degree of abnormal flora, persistent or recurrent BV, peripartum infections, and long-term follow-up evaluation.

Study quality assessment

We developed a quality assessment tool for studies of clindamycin effectiveness using the recommendations of Health Technology Assessment for the identification of systematic reviews.139 The format for the quality assessment tool previously has been used in a systematic review of the efficacy of nifedipine as a tocolytic.140,141 The quality of study methods was assessed with a tailored quality checklist that structured items in 2 broad categories: topic-specific or method-specific items. Furthermore, these items were divided into 3 general subcategories: selection bias, performance bias, and measurement bias. All quality determinations were scored as (1) adequate, (2) inadequate, or (3) not stated in the article. Consensus among the authors was reached through discussion and reevaluation.

Data abstraction

Two reviewers (R.F.L. and C.N.) scanned the abstracts and titles. Hard copies for all potentially relevant articles were acquired and evaluated independently by the 2 reviewers; authorship of the articles was not blinded. All outcome data were extracted independently, in duplicate form, by 2 reviewers. Information was extracted on study methods, study group demographics, intervention details (dose, type, placebo, no treatment), the use of rescreening and retreatment in the studies, and the outcomes (number of outcome events). Consensus among the authors was reached through discussion and reevaluation.

Statistical analysis

Data from each of the studies considered in this study were organized in 2 × 2 contingency tables that contained the number of patients who were classified according to pregnancy outcome and the clindamycin treatment (treated, not treated). We calculated the summary relative risk (RR) for dichotomous data and weighted mean difference for continuous data with associated 95% CIs. Two prespecified subgroup analyses were performed to compare clindamycin with placebo/no treatment according to the route of administration (vaginal vs oral) and re-treatment (yes vs no). In addition, we conducted sensitivity analyses to explore the robustness of the findings for the primary outcome according to a statistical model (fixed-effects vs random-effects), use of placebo (yes vs no), and study quality (high vs not high). However, the sensitivity analysis according to study quality was not performed because all trials that were included were considered as high quality.

Heterogeneity of the results among studies was tested with the quantity I2, which describes the percentage of total variation across studies that is due to heterogeneity rather than chance.142 A value of 0% indicates no observed heterogeneity, whereas I2 values of ≥50% indicate a substantial level of heterogeneity.142 We planned to pool data across studies using the fixed-effects models if substantial statistical heterogeneity was not present. We used random-effects models to pool data across studies if I2 values were ≥50%.

We assessed publication and related biases visually by examining the symmetry of funnel plots and statistically by using the test of Egger et al.143 The larger the deviation of the intercept of the regression line from zero, the greater the asymmetry and the more likely it was that the metaanalysis would yield biased estimates of effect. As suggested by Egger et al,143 we considered a probability value of < .1 to indicate significant asymmetry.

We also calculated the number that was needed to treat (NNT) for an additional beneficial outcome with its 95% confidence intervals (CIs) for outcomes in which the treatment effect was significant at the 5% level (the 95% CI for the absolute risk difference did not include zero).144 NNT was computed from the results of metaanalysis of RRs: NNT = 1/control group event rate × (1-RR).

In this review, NNT for an additional beneficial outcome is the number of women with abnormal vaginal flora who need to be treated with clindamycin at <22 weeks of gestation rather than with placebo or no treatment to prevent 1 case of spontaneous PTB at <37 weeks of gestation or 1 LM between 16 and 23 completed weeks of gestation. Analyses were performed with the Review Manager (RevMan; software version 5.0.23; The Nordic Cochrane Centre, Copenhagen, Denmark).


Literature identification

The flow of the electronic literature search is shown in Figure 1. Of the 428 potentially relevant citations that were identified, 414 were excluded based on the title or on review of the abstract. Based on abstract review, hard copies of 14 articles were obtained. After a detailed review, 5 studies fulfilled the inclusion criteria and are included in the analysis.80,8587,145 Of the 9 studies that were excluded, 2 were subgroup analyses of larger studies;75,79 1 article was not a randomized controlled trial;84 4 trials included patients who were screened and treated at >22 weeks of gestation;74,77,81,105 1 trial was a conference abstract146 of 1 of the included studies,85 and 1 article was an observational study.102 We contacted the first authors of 3 trials74,81,105 to request further information. None of these authors were able to provide data for the subgroup of women who were treated at <22 weeks of gestation, so these studies were excluded from the primary analysis. The 5 trials comprised a total of 2346 women.

Flowchart of literature search

Study quality assessment

The results of the evaluation of the studies’ adherence to the criteria within the 2 domains of quality (method- and topic-specific items) are presented in Table 1. For all the method-specific items of quality, most of the studies were adequate. For 11 of the 16 topic-specific items of quality, most of the studies were considered adequate. In 14 of the 16 topic-specific items of quality, none of the studies were considered inadequate, although a number of studies failed to state data on reference items of quality.

Assessment of quality items

Characteristics of included studies

The characteristics of the included studies are shown in Table 2. Two studies were performed in the United Kingdom85,87 and 1 each in Finland,80 Austria,145 and Sweden.86 In 4 studies, CVC was used;80,85,86,145 only 1 study used clindamycin orally.87 No study used a combination of both oral and CVC. Three studies compared clindamycin with placebo,80,85,87 and 2 studies compared clindamycin with no treatment.86,145 In 4 studies, women with other genital-tract infections were treated but excluded from the study;80,8587 however, in one study, women with Candidiasis or Trichomoniasis were treated and included in the study.145 Nevertheless, it was possible to extract the outcome data on those women with BV alone who were allocated to receive clindamycin or no treatment, so these were included in the analysis.145 Four of the studies rescreened,80,85,86,145 but at different time intervals; 3 studies re-treated if abnormal flora was still present after rescreening.85,86,145 Ugwumadu et al87 did not rescreen or re-treat. Kekki et al80 rescreened 1 week after treatment and again between 30 and 36 weeks of gestation but did not re-treat. Lamont et al85 rescreened 20–24 days after the first course of treatment and re-treated with a 7-day course of CVC or placebo according to the original randomization. Kiss et al145 rescreened between 24 and 27 completed weeks of gestation and, if BV were still present, re-treated with a 7-day course of oral clindamycin, 300 mg twice daily. Larsson et al86 rescreened the intervention group at 24 and 31 weeks of gestation (±2 weeks). If BV or intermediate flora were present, a repeat 7-day course of CVC was administered.

Characteristics of included studies

PTB at <37 weeks of gestation was the primary outcome of all 5 studies,80,8587,145 2 of which86,87 reported PTB as <33 completed weeks of gestation and LM. Two studies commented on mean or median birthweight and very low birthweight,85,87 and 3 studies commented on low birthweight.8587 Three studies commented on gestational age or prolongation of gestation.8587 Three studies commented on admission to the NICU,8587 and 1 study carried out a cost-benefit analysis.86 One of the studies provided data on the success of treatment according to the degree of abnormal flora,87 and another study provided data on outcome after persistent or recurrent BV and peripartum infections.80 Only one study provided data on long-term follow-up evaluation.86

Primary outcomes

Overall, 44 of 1183 women (3.7%) who received clindamycin delivered at <37 completed weeks of gestation, compared with 72 of 1163 (6.2%) in the control group (pooled RR, 0.60; 95% CI, 0.42–86; P<.001; Figure 2). Clindamycin was also associated with a significantly reduced risk of LM (2 studies; RR, 0.20; 95% CI, 0.05–0.76) and a significant increase in gestational age at birth (2 studies; weighted mean difference, 0.64 weeks; 95% CI, 0.28–1.01; Table 3). Forty women with abnormal vaginal flora who were treated at <22 weeks of gestation with clindamycin, rather than with placebo, were needed to prevent 1 case of spontaneous PTB (95% CI, 25–121). The corresponding NNT for LM is 66 (95% CI, 47–228).

Preterm birth at <37 weeks of gestation (5 studies; fixed effects model)
Effect of clindamycin on spontaneous preterm birth and perinatal/maternal outcomes

Sensitivity analysis

Having obtained no additional data from the trials that included women who were screened and treated at >22 weeks of gestation,74,81,105 we performed a sensitivity analysis by adding data for 100 women from the trial by Guaschino et al81 (mean gestational age at enrollment, 19.2 weeks) and 302 women from the trial by Joesoef et al74 who were enrolled at <21 weeks of gestation. Women from the study by McGregor et al105 were not included in this sensitivity analysis because the mean gestational age at enrollment was 21.5 weeks. We assumed that frequencies of PTB at <37 weeks of gestation in clindamycin and placebo groups were similar to those of women of all gestational ages who were enrolled in each group. The significantly decreased risk of PTB at <37 weeks of gestation was demonstrated even in this sensitivity analysis (7 studies; 2748 women; RR, 0.72; 95% CI, 0.54–0.96; I2, 40%).

The random-effects analysis of the primary outcome of spontaneous PTB at <37 weeks of gestation yielded an effect size similar in magnitude and direction to that obtained from the fixed-effects analysis, although it was not significant (RR, 0.64; 95% CI, 0.39–1.05; Table 4). The decrease in the risk of PTB at <37 weeks of gestation was nominally greater in trials that used placebo (RR, 0.55; 95% CI, 0.27–1.11) than in trials that did not use placebo (RR, 0.87; 95% CI, 0.45–1.68).

Sensitivity and subgroup analysis of the effect of clindamycin on spontaneous preterm birth at <37 weeks of gestation

The significantly decreased risk of PTB at <37 weeks of gestation was demonstrated in the subgroup of 1 trial (485 women) that used oral clindamycin (RR, 0.39; 95% CI, 0.20–0.76). Nevertheless, no statistically significant differences between groups were seen in the subgroup of trials that used vaginal clindamycin (4 trials; RR, 0.73; 95% CI, 0.47–1.14) or that used (3 trials; RR, 0.63; 95% CI, 0.38–1.04) or did not use (2 trials; RR, 0.67; 95% CI, 0.21–2.18) re-treatment, although this may be due to the weighting of the trial of Ugwumadu et al.87

Secondary outcomes

There was no overall difference in the risk of PTB at <33 weeks of gestation, low birthweight, very low birthweight, admission to NICU, stillbirth, peripartum infection, and adverse effects, although these outcomes were recorded in only 1 or 2 trials.

Larsson et al86 demonstrated that the mean number of days spent in the NICU was 45 for those in the control group compared with 18 for those who received clindamycin (P = .14) and the cumulative days were 223 and 70, respectively. With an estimated cost of $1602 per day in the NICU, the additional cost for the control group was approximately $245,136.

Clindamycin appeared to be most effective the greater the degree of abnormal flora. In women with the highest Nugent score (10), those who received clindamycin had a 5.4% rate of PTB and LM, compared with 35.7% in those who received placebo.87

In one study, BV persisted in 31% (115 of 375) and recurred in 7% (26 of 375) of the study population.80 The overall rate of PTB and peripartum infection was almost 3 times higher in women in whom BV persisted or recurred during pregnancy (40 of 141; 28%) compared with those in whom BV was cured (12 of 121; 10%; odds ratio, 2.9; 95% CI, 1.3–5.2). Excluding women with intermediate Gram stain findings and including only those who attended both follow-up visits, the rate of PTB was 15% (4 of 26) in the subgroup in which BV was first cured but later recurred, compared with only 2% (2 of 121) in the subgroup in which BV did not recur (odds ratio, 9.3; 95% CI, 1.6–53.5). Kekki et al80 rescreened 1 week after treatment and again between 30 and 36 weeks of gestation but did not re-treat. Nevertheless, 21 women (6%) were given additional CVC for what they described as “suspected symptomatic BV during the rest of the pregnancy,” although this was not defined. Kiss et al145 found that BV alone persisted in approximately 10% of women (44/447). After rescreening at 23 weeks, Larsson et al86 found that BV had resolved in 70% of women; therefore, 30% of the women were re-treated. At 31 weeks of gestation, 10% of the women had experienced relapse and were again re-treated.

One study reported on long-term outcomes of preterm (but not term) infants.86 Twenty-one preterm infants were followed up to 4 years. Among children in the control group, 1 child had retrolental fibroplasia that required strong eyeglasses, and 1 child was diagnosed with bronchopulmonary dysplasia in the neonatal period, but persisted at 4 years of age. No severe treatment-related adverse events were noted.86 All funnel plots showed no asymmetry, either visually or in terms of statistical significance (P > .10 for all, by Egger test143).


Principal findings of the study

This systematic review and metaanalysis of randomized clinical trials shows that when clindamycin is administered to pregnant women with evidence of BV before 22 weeks of gestation: (1) the rate of PTB before 37 weeks of gestation is significantly lower than in the control group. The reduction in the risk of PTB before 37 weeks of gestation was only statistically significant for oral clindamycin but not for vaginal clindamycin; (2) the mean gestational age at delivery was significantly higher in women treated with clindamycin than those allocated to the control group; and (3) the rate of LM was lower (clindamycin vs control group) than in the control group.

Strengths of the study

This study used rigorous methods for performing a systematic review of randomized controlled trials, used a broad literature search, assessed the quality of the studies and is based on studies that have low-to-moderate statistical heterogeneity. Moreover, the robustness of the results for the primary outcome of spontaneous PTB before 37 weeks was examined after performing a sensitivity analysis by adding hypothetical data from 2 excluded studies.

Metronidazole vs clindamycin for the treatment of BV

Although both antibiotics have been recommended for the treatment of symptomatic BV,147 their antimicrobial spectrum is not identical. Clindamycin and other macrolides have a broader antimicrobial activity against organisms involved in BV, including Mobiluncus spp. and mycoplasmas.98,148151 Importantly, these antibiotics have antiinflammatory properties.152156 Patients with the highest Nugent score (who have the most serious disruption in the microbial ecosystem of the vagina, and in which Mobiluncus spp. is frequently found) had a significantly lower rate of PTB when treated with clindamycin, in comparison with those in the placebo group (5.4% vs 35.7%).87 Such observation is in keeping with a subgroup analysis of another study,85 in which women with a grade III Gram stain (Nugent score, 7–10) responded better to clindamycin than those who had intermediate flora (grade II Gram stain, Nugent score 4–6).157

The cure rate of BV after treatment with oral clindamycin has been reported to be as high as 90%,158 while the cure/improvement rate for CVC is 70.8%.134 The 70.8–90% appears better than the 40–77% cure rate after a 2-day course of metronidazole,78,159 or the use of clindamycin cream late in pregnancy.74,160 Two factors seem to influence response to therapy: (1) choice of antibiotic; and (2) gestational age at which it is administered.

Another issue which has not received full attention is whether there is a need to follow patients, confirm that treatment has been effective and the detection of recurrence and appropriate retreatment. Both antimicrobials can cure BV in a large number of women, but the condition can recur, and a second treatment 3–6 weeks after eradication is still able to cure or improve BV in 50% of the patients in whom the condition persisted or recurred (Lamont RF, Taylor-Robinson D, unpublished personal communication, 2009). However, there is no solid evidence that this can lead to a reduction in the rate of spontaneous PTB.

The route of administration of clindamycin appears to be important. Vaginal administration delivers the highest concentration of the antibiotic to the site in which the vaginal ecosystem has changed. If microorganisms have gained access to the endometrium/decidua, CVC may not be effective at this site, and oral therapy may be beneficial. It is noteworthy that, in this review, CVC administration was not associated with a statistically significant reduction in the rate of PTB.

A potential drawback of clindamycin treatment is the risk for C. difficile; however, this complication has also been reported with other antibiotics.161 The vaginal preparation of clindamycin has limited systemic absorption (only 4%),162 and therefore, appears to be safer than oral clindamycin.134

Insofar as metronidazole, in vitro studies have demonstrated that metronidazole and other nitroimidazoles are largely inactive against Gardnerella vaginalis, Mycoplasma hominis, Ureaplasma urealyticum,163,164 and Atopobium vaginae.165,166 Similarly, these compounds have little or no activity against streptococci or Staphylococcus aureus.167 Yet, metronidazole administration to women with symptomatic BV is associated with a treatment success rate similar to clindamycin.168 This has been attributed to the activity of the hydroxy metabolite of the drug in vivo, which is effective against the organisms involved in BV. Another potential explanation is that the administration of metronidazole changes the microbial flora by eradicating bacteria susceptible to it (eg, anaerobes and other organisms), and this favors cure of BV.169

The need to examine the potential value of clindamycin

The role of antibiotics in the prevention of PTB was considered to have promise nearly 2 decades ago. However, the results of several studies in which antibiotics were administered to patients whose genital tract was colonized with particular microorganisms (eg, GBS, Ureaplasma urealyticum, Chlamydia trachomatis, Trichomonas vaginalis) yielded largely negative results. We believe that the primary reason for this is that colonization with GBS,170 Ureaplasma urealyticum,171,172 or infection of the endocervix with Chlamydia trachomatis173 in the absence of a systemic adaptive immune response is not a risk factor for preterm delivery. Therefore, treatment with antibiotics of patients colonized or infected with these organisms should not be expected to reduce the rate of preterm delivery, and that has been proven to be correct.9093 In the case of BV in which there is an increased risk for preterm delivery, such risk is modest and is now known to be affected by gene-environment interactions.114116 For example, patients with symptomatic BV who carry a polymorphism for the tumor necrosis factor-α receptor gene have a significantly increased risk of preterm delivery;114116,174 yet, randomized clinical trials have not taken into consideration the maternal genotype that may confer risk.

Results of clinical trials of antibiotics in patients with BV did not provide clear evidence of benefit,7381 and in some cases, the administration of metronidazole was associated with adverse pregnancy outcome (an excess rate of PTB).88 Alternatively, clindamycin administration early in pregnancy has yielded more promising results.87 Yet, when systematic reviews and metaanalyses have been conducted, all trials have either not been included or the studies have considered metronidazole and clindamycin as equivalent, and gestational age at the initiation of therapy has not always been taken into account. We conducted this metaanalysis to explore whether clindamycin treatment of BV in early pregnancy could be of value for the prevention of PTB.

Does clindamycin prevent PTB and late spontaneous miscarriage in patients with BV?

The findings of this study (Figure 2 and Table 3) suggest that clindamycin administration before 22 weeks reduces the rate of PTB at <37 weeks. However, sensitivity analysis performed according to the statistical model indicated that the reduction in PTB (<37 weeks) was only detected using a fixed effect model (relative risk [RR], 0.60; 95% CI, 0.42–0.86), but not when using a random effect model (RR, 0.64; 95% CI, 0.39–1.05). Although the point estimates of the relative risk are quite similar, the results are not significant in both analyses, and this suggests some instability in the results, probably attributed to heterogeneity of clinical trials (heterogeneity, I2 = 41).

When the outcome was spontaneous PTB <33 weeks of gestation, the reduction in PTB was not statistically significant (0.6% [4/639] vs 1.4% [9/631]). This may reflect a limitation in sample size as treatment was associated with a 2 fold decrease in the rate of PTB. This particular endpoint is important because early PTB is expected to be associated with infection more frequently than late PTB, and most morbidity of preterm neonates is found among those born before 33 weeks of gestation.

Of major interest, is that treatment with clindamycin before 22 weeks was associated with a significant reduction in late spontaneous miscarriage (0.31% [2/639] vs 1.9% [12/631]). Nevertheless, these results are only based on 2 studies (Table 3).

Subgroup analysis indicated that the route of administration of clindamycin is important. Oral clindamycin was associated with a significant 61% reduction in the rate of PTB <37 weeks (4.5% [11/244] vs 11.6% [28/241]). However, this is only based on 1 study.87 Vaginal clindamycin was associated with a nonsignificant 27% reduction in the rate of PTB at <37 weeks (3.5% [33/939] vs 4.8% [44/922]; RR, 0.73; 95% CI, 0.47–1.14; 4 trials).80,85,86,145

Finally, retreatment of BV was not found to have a significant effect on the rate of spontaneous PTB (<37 weeks). This was based on the results of 3 studies, which use retreatment and 2 in which retreatment was not employed (Table 4).

BV as a syndrome

BV has traditionally been considered a single condition in which the vaginal microbial ecosystem has changed, and its presence is associated with a greater risk of adverse pregnancy outcome, and specifically, PTB. However, a number of questions remain about the etiology, pathophysiology, diagnosis and treatment of BV. We have recently proposed that BV is a syndrome, and not a single condition.175 This is based on observations which indicate that the profile of proinflammatory cytokines varies among women with BV diagnosed with a Gram stain. Some women have high concentrations of proinflammatory cytokines, and others do not.118,119,176 The outcome of pregnancy in this subset of patients may vary. Such differences may account, in part, for the negative results of clinical trials. It is possible that the predictive value of the Nugent score for spontaneous PTB may be improved by studying the inflammatory response of patients with BV, or the genotype of the mother for genes involved in the inflammatory response or the microbiome of the vagina.175

Future studies

The results of this systematic review and metaanalysis suggest that some patients with BV may benefit from early treatment with clindamycin. It would seem that oral treatment is superior to vaginal treatment. Additional randomized clinical trials are required to confirm the findings of this metaanalysis. However, a much deeper knowledge of the biology, diagnosis, taxonomy, and response to therapy are required to design such trials. An important conclusion of this review is that some late spontaneous miscarriages may be prevented by treatment with clindamycin. This endpoint should be included in future studies.


Supported in part by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services.


1. Romero R, Sepulveda W, Baumann P, et al. The preterm labor syndrome: biochemical, cytologic, immunologic, pathologic, microbiologic, and clinical evidence that preterm labor is a heterogeneous disease. AmJ Obstet Gynecol. 1993;168:287.
2. Romero R, Mazor M, Munoz H, Gomez R, Galasso M, Sherer DM. The preterm labor syndrome. Ann N Y Acad Sci. 1994;734:414–429. [PubMed]
3. Romero R, Mazor M, Wu YK, et al. Infection in the pathogenesis of preterm labor. Semin Perinatol. 1988;12:262–279. [PubMed]
4. Gibbs RS, Romero R, Hillier SL, Eschenbach DA, Sweet RL. A review of premature birth and subclinical infection. Am J Obstet Gynecol. 1992;166:1515–1528. [PubMed]
5. Minkoff H. Prematurity: infection as an etiologic factor. Obstet Gynecol. 1983;62:137–144. [PubMed]
6. Gomez R, Ghezzi F, Romero R, Munoz H, Tolosa JE, Rojas I. Premature labor and intra-amniotic infection. Clinical aspects and role of the cytokines in diagnosis and pathophysiology. Clin Perinatol. 1995;22:281–342. [PubMed]
7. Goldenberg RL, Hauth JC, Andrews WW. Intrauterine infection and preterm delivery. N Engl J Med. 2000;342:1500–1507. [PubMed]
8. Romero R, Espinoza J, Goncalves LF, Kusanovic JP, Friel L, Hassan S. The role of inflammation and infection in preterm birth. Semin Reprod Med. 2007;25:21–39. [PubMed]
9. DiGiulio DB, Romero R, Amogan HP, et al. Microbial prevalence, diversity and abundance in amniotic fluid during preterm labor: a molecular and culture-based investigation. PLoS One. 2008;3:e3056. [PMC free article] [PubMed]
10. DiGiulio DB, Romero R, Kusanovic JP, et al. Prevalence and diversity of microbes in the amniotic fluid, the fetal inflammatory response, and pregnancy outcome in women with preterm pre-labor rupture of membranes. Am J Reprod Immunol. 2010;64:38–57. [PMC free article] [PubMed]
11. Fidel PI, Jr, Romero R, Maymon E, Hertelendy F. Bacteria-induced or bacterial product-induced preterm parturition in mice and rabbits is preceded by a significant fall in serum progesterone concentrations. J Matern F etal Med. 1998;7:222–226. [PubMed]
12. Fidel PL, Jr, Romero R, Wolf N, et al. Systemic and local cytokine profiles in endotoxin-induced preterm parturition in mice. Am J Obstet Gynecol. 1994;170:1467–1475. [PubMed]
13. Hirsch E, Wang H. The molecular pathophysiology of bacterially induced preterm labor: insights from the murine model. J Soc Gynecol Investig. 2005;12:145–155. [PubMed]
14. Lamont RF. Infection and preterm labour. BJOG. 1998;105:1339–1340. [PubMed]
15. Arias F, Rodriquez L, Rayne SC, Kraus FT. Maternal placental vasculopathy and infection: two distinct subgroups among patients with preterm labor and preterm ruptured membranes. Am J Obstet Gynecol. 1993;168:585–591. [PubMed]
16. Kim YM, Bujold E, Chaiworapongsa T, et al. Failure of physiologic transformation of the spiral arteries in patients with preterm labor and intact membranes. Am J Obstet Gynecol. 2003;189:1063–1069. [PubMed]
17. Kim YM, Chaiworapongsa T, Gomez R, et al. Failure of physiologic transformation of the spiral arteries in the placental bed in preterm premature rupture of membranes. Am J Obstet Gynecol. 2002;187:1137–1142. [PubMed]
18. Manabe Y, Sakaguchi M, Mori T. Distention of the uterus activates its multiple pacemakers and induces their coordination. Gynecol Obstet Invest. 1994;38:163–168. [PubMed]
19. Manabe Y, Sakaguchi M, Nakajima A. Initiation of uterine contractions by purely mechanical stretching of the uterus at midpregnancy. Int J Biol Res Pregnancy. 1981;2:63–69. [PubMed]
20. Leguizamon G, Smith J, Younis H, Nelson DM, Sadovsky Y. Enhancement of amniotic cyclooxygenase type 2 activity in women with preterm delivery associated with twins or polyhydramnios. Am J Obstet Gynecol. 2001;184:117–122. [PubMed]
21. Many A, Hill LM, Lazebnik N, Martin JG. The association between polyhydramnios and preterm delivery. Obstet Gynecol. 1995;86:389–391. [PubMed]
22. Kim CJ, Romero R, Kusanovic JP, et al. The frequency, clinical significance, and pathological features of chronic chorioamnionitis: a lesion associated with spontaneous preterm birth. Mod Pathol. 2010;23:1000–1011. [PMC free article] [PubMed]
23. Kim JS, Romero R, Kim MR, et al. Involvement of Hofbauer cells and maternal T cells in villitis of unknown aetiology. Histopathology. 2008;52:457–464. [PMC free article] [PubMed]
24. Kim MJ, Romero R, Kim CJ, et al. Villitis of unknown etiology is associated with a distinct pattern of chemokine up-regulation in the feto-maternal and placental compartments: implications for conjoint maternal allograft rejection and maternal anti-fetal graft-versus-host disease. J Immunol. 2009;182:3919–3927. [PMC free article] [PubMed]
25. Romero R, Kusanovic JP, Munoz H, Gomez R, Lamont RF, Yeo L. Allergy-induced preterm labor after the ingestion of shellfish. J Matern Fetal Neonatal Med. 2010;23:351–359. [PMC free article] [PubMed]
26. Bytautiene E, Romero R, Vedernikov YP, El Zeky F, Saade GR, Garfield RE. Induction of premature labor and delivery by allergic reaction and prevention by histamine H1 receptor antagonist. Am J Obstet Gynecol. 2004;191:1356–1361. [PubMed]
27. Bytautiene E, Vedernikov YP, Saade GR, Romero R, Garfield RE. Endogenous mast cell degranulation modulates cervical contractility in the guinea pig. Am J Obstet Gynecol. 2002;186:438–445. [PubMed]
28. Romero R, Mazor M, Avila C, Quintero R, Munoz H. Uterine “allergy”: a novel mechanism for preterm labor. Am J Obstet Gynecol. 1991;164:375.
29. Hassan SS, Romero R, Vidyadhari D, et al. Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol. 2011;38:18–31. [PMC free article] [PubMed]
30. Mesiano S. Roles of estrogen and progesterone in human parturition. Front Horm Res. 2001;27:86–104. [PubMed]
31. Mesiano S. Myometrial progesterone responsiveness and the control of human parturition. J Soc Gynecol Investig. 2004;11:193–202. [PubMed]
32. Pieber D, Allport VC, Bennett PR. Progesterone receptor isoform A inhibits isoform B-mediated transactivation in human amnion. Eur J Pharmacol. 2001;427:7–11. [PubMed]
33. Hassan SS, Romero R, Berry SM, Dang K, Blackwell SC, Treadwell MC, et al. Patients with an ultrasonographic cervical length < or = 15 mm have nearly a 50% risk of early spontaneous preterm delivery. Am J Obstet Gynecol. 2000;182:1458–1467. [PubMed]
34. Iams JD, Johnson FF, Sonek J, Sachs L, Gebauer C, Samuels P. Cervical competence as a continuum: a study of ultrasonographic cervical length and obstetric performance. Am J Obstet Gynecol. 1995;172:1097–1103. [PubMed]
35. Heath VC, Southall TR, Souka AP, Elisseou A, Nicolaides KH. Cervical length at 23 weeks of gestation: prediction of spontaneous preterm delivery. Ultrasound Obstet Gynecol. 1998;12:312–317. [PubMed]
36. Smith CV, Anderson JC, Matamoros A, Rayburn WF. Transvaginal sonography of cervical width and length during pregnancy. J Ultrasound Med. 1992;11:465–467. [PubMed]
37. Gravett MG, Witkin SS, Haluska GJ, Edwards JL, Cook MJ, Novy MJ. An experimental model for intraamniotic infection and preterm labor in rhesus monkeys. Am J Obstet Gynecol. 1994;171:1660–1667. [PubMed]
38. Hirsch E, Saotome I, Hirsh D. A model of intrauterine infection and preterm delivery in mice. Am J Obstet Gynecol. 1995;172:1598–1603. [PubMed]
39. Romero R, Mazor M, Wu YK, Avila C, Oyarzun E, Mitchell MD. Bacterial endotoxin and tumor necrosis factor stimulate prostaglandin production by human decidua. Prostaglandins Leukot Essent Fatty Acids. 1989;37:183–186. [PubMed]
40. Abrahams VM, Bole-Aldo P, Kim YM, et al. Divergent trophoblast responses to bacterial products mediated by TLRs. J Immunol. 2004;173:4286–4296. [PubMed]
41. Abrahams VM, Mor G. Toll-like receptors and their role in the trophoblast. Placenta. 2005;26:540–547. [PubMed]
42. Elovitz MA, Wang Z, Chien EK, Rychlik DF, Phillippe M. A new model for inflammation-induced preterm birth: the role of platelet-activating factor and Toll-like receptor-4. Am J Pathol. 2003;163:2103–2111. [PubMed]
43. Kim YM, Romero R, Chaiworapongsa T, et al. Toll-like receptor-2 and -4 in the chorioamniotic membranes in spontaneous labor at term and in preterm parturition that are associated with chorioamnionitis. Am J Obstet Gynecol. 2004;191:1346–1355. [PubMed]
44. Mor G, Romero R, Aldo PB, Abrahams VM. Is the trophoblast an immune regulator? The role of Toll-like receptors during pregnancy. Crit Rev Immunol. 2005;25:375–388. [PubMed]
45. Kelly RW, Leask R, Calder AA. Choriodecidual production of interleukin-8 and mechanism of parturition. Lancet. 1992;339:776–777. [PubMed]
46. Romero R, Ceska M, Avila C, Mazor M, Behnke E, Lindley I. Neutrophil attractant/activating peptide-1/interleukin-8 in term and preterm parturition. Am J Obstet Gynecol. 1991;165:813–820. [PubMed]
47. Romero R, Gomez R, Galasso M, et al. Macrophage inflammatory protein-1 alpha in term and preterm parturition: effect of microbial invasion of the amniotic cavity. Am J Reprod Immunol. 1994;32:108–113. [PubMed]
48. Hamill N, Romero R, Gotsch F, et al. Exodus-1 (CCL20): evidence for the participation of this chemokine in spontaneous labor at term, preterm labor, and intrauterine infection. J Perinat Med. 2008;36:217–227. [PMC free article] [PubMed]
49. Nhan-Chang CL, Romero R, Kusanovic JP, et al. A role for CXCL13 (BCA-1) in pregnancy and intra-amniotic infection/inflammation. J Matern Fetal Neonatal Med. 2008;21:763–775. [PMC free article] [PubMed]
50. Romero R, Mazor M, Sepulveda W, Avila C, Copeland D, Williams J. Tumor necrosis factor in preterm and term labor. Am J Obstet Gynecol. 1992;166:1576–1587. [PubMed]
51. Romero R, Manogue KR, Mitchell MD, et al. Infection and labor: IV, cachectin-tumor necrosis factor in the amniotic fluid of women with intraamniotic infection and preterm labor. Am J Obstet Gynecol. 1989;161:336–341. [PubMed]
52. Romero R, Avila C, Santhanam U, Sehgal PB. Amniotic fluid interleukin 6 in preterm labor: association with infection. J Clin Invest. 1990;85:1392–1400. [PMC free article] [PubMed]
53. Romero R, Brody DT, Oyarzun E, et al. Infection and labor. III. Interleukin-1: a signal for the onset of parturition. Am J Obstet Gynecol. 1989;160:1117–1123. [PubMed]
54. Meis PJ, Goldenberg RL, Mercer B, et al. The preterm prediction study: significance of vaginal infections: National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Am J Obstet Gynecol. 1995;173:1231–1235. [PubMed]
55. Hay P, Czeizel AE. Asymptomatic trichomonas and candida colonization and pregnancy outcome. Best Pract Res Clin Obstet Gynaecol. 2007;21:403–409. [PubMed]
56. Andrews WW, Klebanoff MA, Thom EA, et al. Midpregnancy genitourinary tract infection with Chlamydia trachomatis: association with subsequent preterm delivery in women with bacterial vaginosis and Trichomonas vaginalis. Am J Obstet Gynecol. 2006;194:493–500. [PubMed]
57. Cotch MF, Pastorek JG, Nugent RP, et al. Trichomonas vaginalis associated with low birth weight and preterm delivery. The Vaginal Infections and Prematurity Study Group. Sex Transm Dis. 1997;24:353–360. [PubMed]
58. Donders GG, Desmyter J, De Wet DH, Van Assche FA. The association of gonorrhoea and syphilis with premature birth and low birth-weight. Genitourin Med. 1993;69:98–101. [PMC free article] [PubMed]
59. Association of Chlamydia trachomatis and Mycoplasma hominis with intrauterine growth retardation and preterm delivery. The John Hopkins Study of Cervicitis and Adverse Pregnancy Outcome. Am J Epidemiol. 1989;129:1247–1257. [PubMed]
60. Breugelmans M, Vancutsem E, Naessens A, Laubach M, Foulon W. Association of abnormal vaginal flora and Ureaplasma species as risk factors for preterm birth: a cohort study. Acta Obstet Gynecol Scand. 2010;89:256–260. [PubMed]
61. Kimberlin DF, Andrews WW. Bacterial vaginosis: association with adverse pregnancy outcome. Semin Perinatol. 1998;22:242–250. [PubMed]
62. Lamont RF, Taylor-Robinson D. The role of bacterial vaginosis, aerobic vaginitis, abnormal vaginal flora and the risk of preterm birth. BJOG. 2010;117:119–121. [PubMed]
63. Donders GG, Bosmans E, Dekeersmaecker A, Vereecken A, Van BB, Spitz B. Pathogenesis of abnormal vaginal bacterial flora. Am J Obstet Gynecol. 2000;182:872–878. [PubMed]
64. Donati L, Di VA, Nucci M, et al. Vaginal microbial flora and outcome of pregnancy. Arch Gynecol Obstet. 2010;281:589–600. [PubMed]
65. Minkoff H, Grunebaum AN, Schwarz RH, et al. Risk factors for prematurity and premature rupture of membranes: a prospective study of the vaginal flora in pregnancy. Am J Obstet Gynecol. 1984;150:965–972. [PubMed]
66. Donders GG, Vereecken A, Bosmans E, Dekeersmaecker A, Salembier G, Spitz B. Definition of a type of abnormal vaginal flora that is distinct from bacterial vaginosis: aerobic vaginitis. BJOG. 2002;109:34–43. [PubMed]
67. Minkoff H, Grunebaum A, Feldman J, Cummings M, McCormack WM. Relationship of vaginal pH and Papanicolaou smear results to vaginal flora and pregnancy outcome. Int J Gynaecol Obstet. 1987;25:17–23. [PubMed]
68. Carey JC, Klebanoff MA. Is a change in the vaginal flora associated with an increased risk of preterm birth? Am J Obstet Gynecol. 2005;192:1341–1346. [PubMed]
69. Mass SB, Brennan JP, Silverman N, van Hoeven KH. Association between a shift in vaginal flora on Papanicolaou smear and acute chorioamnionitis and preterm delivery. Diagn Cytopathol. 1999;21:7–9. [PubMed]
70. Usui R, Ohkuchi A, Matsubara S, et al. Vaginal lactobacilli and preterm birth. J Perinat Med. 2002;30:458–466. [PubMed]
71. Hay PE, Lamont RF, Taylor-Robinson D, Morgan DJ, Ison C, Pearson J. Abnormal bacterial colonisation of the genital tract and subsequent preterm delivery and late miscarriage. BMJ. 1994;308:295–298. [PMC free article] [PubMed]
72. McDonald HM, O’Loughlin JA, Jolley PT, Vigneswaran R, McDonald PJ. Changes in vaginal flora during pregnancy and association with preterm birth. J Infect Dis. 1994;170:724–728. [PubMed]
73. Duff P, Lee ML, Hillier SL, Herd LM, Krohn MA, Eschenbach DA. Amoxicillin treatment of bacterial vaginosis during pregnancy. Obstet Gynecol. 1991;77:431–435. [PubMed]
74. Joesoef MR, Hillier SL, Wiknjosastro G, et al. Intravaginal clindamycin treatment for bacterial vaginosis: effects on preterm delivery and low birth weight. Am J Obstet Gynecol. 1995;173:1527–1531. [PubMed]
75. Rosenstein IJ, Morgan DJ, Lamont RF, et al. Effect of intravaginal clindamycin cream on pregnancy outcome and on abnormal vaginal microbial flora of pregnant women. Infect Dis Obstet Gynecol. 2000;8:158–165. [PMC free article] [PubMed]
76. McDonald HM, O’Loughlin JA, Vigneswaran R, et al. Impact of metronidazole therapy on preterm birth in women with bacterial vaginosis flora (Gardnerella vaginalis): a randomised, placebo controlled trial. BJOG. 1997;104:1391–1397. [PubMed]
77. Vermeulen GM, Bruinse HW. Prophylactic administration of clindamycin 2% vaginal cream to reduce the incidence of spontaneous preterm birth in women with an increased recurrence risk: a randomised placebo-controlled double-blind trial. BJOG. 1999;106:652–657. [PubMed]
78. Carey JC, Klebanoff MA, Hauth JC, et al. Metronidazole to prevent preterm delivery in pregnant women with asymptomatic bacterial vaginosis: National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med. 2000;342:534–540. [PubMed]
79. Kurkinen-Raty M, Vuopala S, Koskela M, et al. A randomised controlled trial of vaginal clindamycin for early pregnancy bacterial vaginosis. BJOG. 2000;107:1427–1432. [PubMed]
80. Kekki M, Kurki T, Pelkonen J, Kurkinen-Raty M, Cacciatore B, Paavonen J. Vaginal clindamycin in preventing preterm birth and peripartal infections in asymptomatic women with bacterial vaginosis: a randomized, controlled trial. Obstet Gynecol. 2001;97:643–648. [PubMed]
81. Guaschino S, Ricci E, Franchi M, et al. Treatment of asymptomatic bacterial vaginosis to prevent pre-term delivery: a randomised trial. Eur J Obstet Gynecol Reprod Biol. 2003;110:149–152. [PubMed]
82. Hauth JC, Goldenberg RL, Andrews WW, DuBard MB, Copper RL. Reduced incidence of preterm delivery with metronidazole and erythromycin in women with bacterial vaginosis. N Engl J Med. 1995;333:1732–1736. [PubMed]
83. Morales WJ, Schorr S, Albritton J. Effect of metronidazole in patients with preterm birth in preceding pregnancy and bacterial vaginosis: a placebo-controlled, double-blind study. Am J Obstet Gynecol. 1994;171:345–347. [PubMed]
84. McGregor JA, French JI, Parker R, et al. Prevention of premature birth by screening and treatment for common genital tract infections: results of a prospective controlled evaluation. Am J Obstet Gynecol. 1995;173:157–167. [PubMed]
85. Lamont RF, Duncan SL, Mandal D, Bassett P. Intravaginal clindamycin to reduce preterm birth in women with abnormal genital tract flora. Obstet Gynecol. 2003;101:516–522. [PubMed]
86. Larsson PG, Fahraeus L, Carlsson B, Jakobsson T, Forsum U. Late miscarriage and preterm birth after treatment with clindamycin: a randomised consent design study according to Zelen. BJOG. 2006;113:629–637. [PubMed]
87. Ugwumadu A, Manyonda I, Reid F, Hay P. Effect of early oral clindamycin on late miscarriage and preterm delivery in asymptomatic women with abnormal vaginal flora and bacterial vaginosis: a randomised controlled trial. Lancet. 2003;361:983–988. [PubMed]
88. Klebanoff MA, Carey JC, Hauth JC, et al. Failure of metronidazole to prevent preterm delivery among pregnant women with asymptomatic Trichomonas vaginalis infection. N Engl J Med. 2001;345:487–493. [PubMed]
89. Grable IA, Garcia PM, Perry D, Socol ML. Group B Streptococcus and preterm premature rupture of membranes: a randomized, double-blind clinical trial of antepartum ampicillin. Am J Obstet Gynecol. 1996;175:1036–1042. [PubMed]
90. Klebanoff MA, Regan JA, Rao AV, et al. Outcome of the Vaginal Infections and Prematurity Study: results of a clinical trial of erythromycin among pregnant women colonized with group B streptococci. Am J Obstet Gynecol. 1995;172:1540–1545. [PubMed]
91. Ogasawara KK, Goodwin TM. Efficacy of azithromycin in reducing lower genital Ureaplasma urealyticum colonization in women at risk for preterm delivery. J Matern Fetal Med. 1999;8:12–16. [PubMed]
92. Eschenbach DA, Nugent RP, Rao AV, et al. A randomized placebo-controlled trial of erythromycin for the treatment of Ureaplasma urealyticum to prevent premature delivery. The Vaginal Infections and Prematurity Study Group. Am J Obstet Gynecol. 1991;164:734–742. [PubMed]
93. Martin DH, Eschenbach DA, Cotch MF, et al. Double-Blind Placebo-Controlled Treatment Trial of Chlamydia trachomatis Endocervical Infections in Pregnant Women. Infect Dis Obstet Gynecol. 1997;5:10–17. [PMC free article] [PubMed]
94. Romero R, Mazor M, Oyarzun E, Sirtori M, Wu YK, Hobbins JC. Is there an association between colonization with group B Streptococcus and prematurity? J Reprod Med. 1989;34:797–801. [PubMed]
95. Romero R, Sibai B, Caritis S, et al. Antibiotic treatment of preterm labor with intact membranes: a multicenter, randomized, double-blinded, placebo-controlled trial. Am J Obstet Gynecol. 1993;169:764–774. [PubMed]
96. Romero R, Sirtori M, Oyarzun E, et al. Infection and labor. V. Prevalence, microbiology, and clinical significance of intraamniotic infection in women with preterm labor and intact membranes. Am J Obstet Gynecol. 1989;161:817–824. [PubMed]
97. Lamont RF. Bacterial vaginosis. In: Critchley H, Bennett P, Thornton S, editors. Preterm birth. London: RCOG Press; 2004. pp. 163–180.
98. Hillier SL, Holmes KK. Bacterial vaginosis. In: Holmes KK, Markowitz LE, Spellacy W, Wiggins R, editors. Sexually transmitted diseases, 2nd ed. New York: McGraw-Hill; 1990. pp. 547–550.
99. Eschenbach DA, Gravett MG, Chen KC, Hoyme UB, Holmes KK. Bacterial vaginosis during pregnancy: an association with prematurity and postpartum complications. Scand J Urol Nephrol Suppl. 1984;86:213–222. [PubMed]
100. McDonald HM, O’Loughlin JA, Jolley P, Vigneswaran R, McDonald PJ. Prenatal microbiological risk factors associated with preterm birth. BJOG. 1992;99:190–196. [PubMed]
101. Kurki T, Sivonen A, Renkonen OV, Savia E, Ylikorkala O. Bacterial vaginosis in early pregnancy and pregnancy outcome. Obstet Gynecol. 1992;80:173–177. [PubMed]
102. Riduan JM, Hillier SL, Utomo B, Wiknjosastro G, Linnan M, Kandun N. Bacterial vaginosis and prematurity in Indonesia: association in early and late pregnancy. Am J Obstet Gynecol. 1993;169:175–178. [PubMed]
103. Hillier SL, Nugent RP, Eschenbach DA, et al. Association between bacterial vaginosis and preterm delivery of a low-birth-weight infant: the Vaginal Infections and Prematurity Study group. N Engl J Med. 1995;333:1737–1742. [PubMed]
104. Holst E, Goffeng AR, Andersch B. Bacterial vaginosis and vaginal microorganisms in idiopathic premature labor and association with pregnancy outcome. J Clin Microbiol. 1994;32:176–186. [PMC free article] [PubMed]
105. McGregor JA, French JI, Jones W, et al. Bacterial vaginosis is associated with prematurity and vaginal fluid mucinase and sialidase: results of a controlled trial of topical clindamycin cream. Am J Obstet Gynecol. 1994;170:1048–1059. [PubMed]
106. Gratacos E, Figueras F, Barranco M, et al. Spontaneous recovery of bacterial vaginosis during pregnancy is not associated with an improved perinatal outcome. Acta Obstet Gynecol Scand. 1998;77:37–40. [PubMed]
107. Jacobsson B, Pernevi P, Chidekel L, Jorgen Platz-Christensen J. Bacterial vaginosis in early pregnancy may predispose for preterm birth and postpartum endometritis. Acta Obstet Gynecol Scand. 2002;81:1006–1010. [PubMed]
108. Vogel I, Thorsen P, Hogan VK, Schieve LA, Jacobsson B, Ferre CD. The joint effect of vaginal Ureaplasma urealyticum and bacterial vaginosis on adverse pregnancy outcomes. Acta Obstet Gynecol Scand. 2006;85:778–785. [PubMed]
109. Gravett MG, Nelson HP, DeRouen T, Critchlow C, Eschenbach DA, Holmes KK. Independent associations of bacterial vaginosis and Chlamydia trachomatis infection with adverse pregnancy outcome. JAMA. 1986;256:1899–1903. [PubMed]
110. Gravett MG, Hummel D, Eschenbach DA, Holmes KK. Preterm labor associated with subclinical amniotic fluid infection and with bacterial vaginosis. Obstet Gynecol. 1986;67:229–237. [PubMed]
111. Newton ER, Piper J, Peairs W. Bacterial vaginosis and intraamniotic infection. Am J Obstet Gynecol. 1997;176:672–677. [PubMed]
112. Martius J, Eschenbach DA. The role of bacterial vaginosis as a cause of amniotic fluid infection, chorioamnionitis and prematurity—a review. Arch Gynecol Obstet. 1990;247:1–13. [PubMed]
113. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet. 2008;371:75–84. [PubMed]
114. Macones GA, Parry S, Elkousy M, Clothier B, Ural SH, Strauss JF., III A polymorphism in the promoter region of TNF and bacterial vaginosis: preliminary evidence of gene-environment interaction in the etiology of spontaneous preterm birth. Am J Obstet Gynecol. 2004;190:1504–1508. [PubMed]
115. Gomez LM, Sammel MD, Appleby DH, et al. Evidence of a gene-environment interaction that predisposes to spontaneous preterm birth: a role for asymptomatic bacterial vaginosis and DNA variants in genes that control the inflammatory response. Am J Obstet Gynecol. 2010;202:386. [PubMed]
116. Romero R, Chaiworapongsa T, Kuivaniemi H, Tromp G. Bacterial vaginosis, the inflammatory response and the risk of preterm birth: a role for genetic epidemiology in the prevention of preterm birth. Am J Obstet Gynecol. 2004;190:1509–1519. [PubMed]
117. Fidel P, Ghezzi F, Romero R, et al. The effect of antibiotic therapy on intrauterine infection-induced preterm parturition in rabbits. J Matern Fetal Neonatal Med. 2003;14:57–64. [PubMed]
118. Cauci S, Guaschino S, De AD, et al. Interrelationships of interleukin-8 with interleukin-1beta and neutrophils in vaginal fluid of healthy and bacterial vaginosis positive women. Mol Hum Reprod. 2003;9:53–58. [PubMed]
119. Donders GG, Vereecken A, Bosmans E, Spitz B. Vaginal cytokines in normal pregnancy. Am J Obstet Gynecol. 2003;189:1433–1438. [PubMed]
120. Gomez R, Romero R, Ghezzi F, Yoon BH, Mazor M, Berry SM. The fetal inflammatory response syndrome. Am J Obstet Gynecol. 1998;179:194–202. [PubMed]
121. Gotsch F, Romero R, Kusanovic JP, et al. The fetal inflammatory response syndrome. Clin Obstet Gynecol. 2007;50:652–683. [PubMed]
122. Kim SK, Romero R, Chaiworapongsa T, et al. Evidence of changes in the immunophenotype and metabolic characteristics (intracellular reactive oxygen radicals) of fetal, but not maternal, monocytes and granulocytes in the fetal inflammatory response syndrome. J Perinat Med. 2009;37:543–552. [PMC free article] [PubMed]
123. Cardenas I, Means RE, Aldo P, et al. Viral infection of the placenta leads to fetal inflammation and sensitization to bacterial products predisposing to preterm labor. J Immunol. 2010;185:1248–1257. [PMC free article] [PubMed]
124. Guise JM, Mahon SM, Aickin M, Helfand M, Peipert JF, Westhoff C. Screening for bacterial vaginosis in pregnancy. Am J Prev Med. 2001;20:62–72. [PubMed]
125. Hutzal CE, Boyle EM, Kenyon SL, et al. Use of antibiotics for the treatment of preterm parturition and prevention of neonatal morbidity: a metaanalysis. Am J Obstet Gynecol. 2008;199:620–628. [PubMed]
126. Koumans EH, Markowitz LE, Hogan V. Indications for therapy and treatment recommendations for bacterial vaginosis in nonpregnant and pregnant women: a synthesis of data. Clin Infect Dis. 2002;35:S152–S172. [PubMed]
127. Leitich H, Brunbauer M, Bodner-Adler B, Kaider A, Egarter C, Husslein P. Antibiotic treatment of bacterial vaginosis in pregnancy: a meta-analysis. Am J Obstet Gynecol. 2003;188:752–758. [PubMed]
128. McDonald HM, Brocklehurst P, Gordon A. Antibiotics for treating bacterial vaginosis in pregnancy. Cochrane Database Syst Rev. 2007;1 CD000262. [PMC free article] [PubMed]
129. Okun N, Gronau KA, Hannah ME. Antibiotics for bacterial vaginosis or Trichomonas vaginalis in pregnancy: a systematic review. Obstet Gynecol. 2005;105:857–868. [PubMed]
130. Riggs MA, Klebanoff MA. Treatment of vaginal infections to prevent preterm birth: a meta-analysis. Clin Obstet Gynecol. 2004;47:796–807. [PubMed]
131. Simcox R, Sin WT, Seed PT, Briley A, Shennan AH. Prophylactic antibiotics for the prevention of preterm birth in women at risk: a meta-analysis. Aust N Z J Obstet Gynaecol. 2007;47:368–377. [PubMed]
132. Swadpanich U, Lumbiganon P, Prasertcharoensook W, Laopaiboon M. Antenatal lower genital tract infection screening and treatment programs for preventing preterm delivery. Cochrane Database Syst Rev. 2008;2 CD006178. [PubMed]
133. Varma R, Gupta JK. Antibiotic treatment of bacterial vaginosis in pregnancy: multiple meta-analyses and dilemmas in interpretation. Eur J Obstet Gynecol Reprod Biol. 2006;124:10–14. [PubMed]
134. Lamont RF, Jones BM, Mandal D, Hay PE, Sheehan M. The efficacy of vaginal clindamycin for the treatment of abnormal genital tract flora in pregnancy. Infect Dis Obstet Gynecol. 2003;11:181–189. [PMC free article] [PubMed]
135. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339 b2700. [PubMed]
136. Spiegel CA, Amsel R, Holmes KK. Diagnosis of bacterial vaginosis by direct Gram stain of vaginal fluid. J Clin Microbiol. 1983;18:170–177. [PMC free article] [PubMed]
137. Nugent RP, Krohn MA, Hillier SL. Reliability of diagnosing bacterial vaginosis is improved by a standardized method of gram stain interpretation. J Clin Microbiol. 1991;29:297–301. [PMC free article] [PubMed]
138. Ison CA, Hay PE. Validation of a simplified grading of Gram stained vaginal smears for use in genitourinary medicine clinics. Sex Transm Infect. 2002;78:413–415. [PMC free article] [PubMed]
139. Centre for Reviews and Dissemination. Undertaking systematic reviews of research on effectiveness. (2nd ed) 2001;(No. 4)
140. Lamont RF, Khan KS, Beattie B, et al. The quality of nifedipine studies used to assess tocolytic efficacy: a systematic review. J Perinat Med. 2005;33:287–295. [PubMed]
141. Lamont RF. A quality assessment tool to evaluate tocolytic studies. BJOG. 2006;113 suppl 3:96–99. [PubMed]
142. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–560. [PMC free article] [PubMed]
143. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–634. [PMC free article] [PubMed]
144. Altman DG. Confidence intervals for the number needed to treat. BMJ. 1998;317:1309–1312. [PMC free article] [PubMed]
145. Kiss H, Petricevic L, Husslein P. Prospective randomised controlled trial of an infection screening programme to reduce the rate of preterm delivery. BMJ. 2004;329:371. [PMC free article] [PubMed]
146. Alvi SA, Lamont RF. Pregnancy outcome following the use of clindamycin intravaginal creams. J Soc Gynecol Invest. 1999;6:S94A.
147. Centers for Disease Control and Prevention. Workowski KA, Berman S. Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep. 2010;59:1–110. [PubMed]
148. Barry AL, Thornsberry C, Jones RN. In vitro activity of a new macrolide, A-56268, compared with that of roxithromycin, erythromycin, and clindamycin. Antimicrob Agents Chemother. 1987;31:343–345. [PMC free article] [PubMed]
149. Spiegel CA, Eschenbach DA, Amsel R, Holmes KK. Curved anaerobic bacteria in bacterial (nonspecific) vaginosis and their response to antimicrobial therapy. J Infect Dis. 1983;148:817–822. [PubMed]
150. Young RA, Gonzalez JP, Sorkin EM. Roxithromycin: a review of its antibacterial activity, pharmacokinetic properties and clinical efficacy. Drugs. 1989;37:8–41. [PubMed]
151. Spiegel CA. Susceptibility of Mobiluncus species to 23 antimicrobial agents and 15 other compounds. Antimicrob Agents Chemother. 1987;31:249–252. [PMC free article] [PubMed]
152. Esterly NB, Furey NL, Flanagan LE. The effect of antimicrobial agents on leukocyte chemotaxis. J Invest Dermatol. 1978;70:51–55. [PubMed]
153. Hand WL, Hand DL, King-Thompson NL. Antibiotic inhibition of the respiratory burst response in human polymorphonuclear leukocytes. Antimicrob Agents Chemother. 1990;34:863–870. [PMC free article] [PubMed]
154. Konno S, Asano K, Kurokawa M, Ikeda K, Okamoto K, Adachi M. Antiasthmatic activity of a macrolide antibiotic, roxithromycin: analysis of possible mechanisms in vitro and in vivo. Int Arch Allergy Immunol. 1994;105:308–316. [PubMed]
155. Mikasa K, Kita E, Sawaki M, et al. The anti-inflammatory effect of erythromycin in zymosan-induced peritonitis of mice. J Antimicrob Chemother. 1992;30:339–348. [PubMed]
156. Takeshita K, Yamagishi I, Harada M, Otomo S, Nakagawa T, Mizushima Y. Immunological and anti-inflammatory effects of clarithromycin: inhibition of interleukin 1 production of murine peritoneal macrophages. Drugs Exp Clin Res. 1989;15:527–533. [PubMed]
157. Rosenstein IJ, Morgan DJ, Sheehan M, Lamont RF, Taylor-Robinson D. Bacterial vaginosis in pregnancy: distribution of bacterial species in different gram-stain categories of the vaginal flora. J Med Microbiol. 1996;45:120–126. [PubMed]
158. Ugwumadu A, Reid F, Hay P, Manyonda I. Natural history of bacterial vaginosis and intermediate flora in pregnancy and effect of oral clindamycin. Obstet Gynecol. 2004;104:114–119. [PubMed]
159. McDonald HM, O’Loughlin JA, Vigneswaran R, Jolley PT, McDonald PJ. Bacterial vaginosis in pregnancy and efficacy of short-course oral metronidazole treatment: a randomized controlled trial. Obstet Gynecol. 1994;84:343–348. [PubMed]
160. Vermeulen GM, van Zwet AA, Bruinse HW. Changes in the vaginal flora after two percent clindamycin vaginal cream in women at high risk of spontaneous preterm birth. BJOG. 2001;108:697–700. [PubMed]
161. McFarland LV. Antibiotic-associated diarrhea: epidemiology, trends and treatment. Future Microbiol. 2008;3:563–578. [PubMed]
162. Borin MT, Powley GW, Tackwell KR, Batts DH. Absorption of clindamycin after intravaginal application of clindamycin phosphate 2% cream. J Antimicrob Chemother. 1995;35:833–841. [PubMed]
163. Goldstein EJ, Citron DM, Merriam CV, Warren YA, Tyrrell KL, Fernandez HT. In vitro activities of Garenoxacin (BMS 284756) against 108 clinical isolates of Gardnerella vaginalis. Antimicrob Agents Chemother. 2002;46:3995–3996. [PMC free article] [PubMed]
164. Xiao JC, Xie LF, Fang SL, et al. Symbiosis of Mycoplasma hominis in Trichomonas vaginalis may link metronidazole resistance in vitro. Parasitol Res. 2006;100:123–130. [PubMed]
165. De Backer E, Dubreuil L, Brauman M, Acar J, Vaneechoutte M. In vitro activity of secnidazole against Atopobium vaginae, an anaerobic pathogen involved in bacterial vaginosis. Clin Microbiol Infect. 2010;16:470–472. [PubMed]
166. Ferris MJ, Masztal A, Aldridge KE, Fortenberry JD, Fidel PL, Jr, Martin DH. Association of Atopobium vaginae, a recently described metronidazole resistant anaerobe, with bacterial vaginosis. BMC Infect Dis. 2004;4:5. [PMC free article] [PubMed]
167. Donders GG, Van Calsteren K, Bellen G, et al. Predictive value for preterm birth of abnormal vaginal flora, bacterial vaginosis and aerobic vaginitis during the first trimester of pregnancy. BJOG. 2009;116:1315–1324. [PubMed]
168. Workowski KA, Berman SM. Centers for Disease Control and Prevention sexually transmitted diseases treatment guidelines. Clin Infect Dis. 2007;44 suppl 3:S73–S76. [PubMed]
169. Bradshaw CS, Morton AN, Hocking J, et al. High recurrence rates of bacterial vaginosis over the course of 12 months after oral metronidazole therapy and factors associated with recurrence. J Infect Dis. 2006;193:1478–1486. [PubMed]
170. Valkenburg-van den Berg AW, Sprij AJ, Dekker FW, Dorr PJ, Kanhai HH. Association between colonization with Group B Streptococcus and preterm delivery: a systematic review. Acta Obstet Gynecol Scand. 2009;88:958–967. [PubMed]
171. Lee SE, Romero R, Kim EC, Yoon BH. A high Nugent score but not a positive culture for genital mycoplasmas is a risk factor for spontaneous preterm birth. J Matern Fetal Neonatal Med. 2009;22:212–217. [PMC free article] [PubMed]
172. Romero R, Mazor M, Oyarzun E, Sirtori M, Wu YK, Hobbins JC. Is genital colonization with Mycoplasma hominis or Ureaplasma urealyticum associated with prematurity/low birth weight? Obstet Gynecol. 1989;73:532–536. [PubMed]
173. Andrews WW, Klebanoff MA, Thom EA, et al. Midpregnancy genitourinary tract infection with Chlamydia trachomatis: association with subsequent preterm delivery in women with bacterial vaginosis and Trichomonas vaginalis. Am J Obstet Gynecol. 2006;194:493–500. [PubMed]
174. Jones NM, Holzman C, Friderici KH, et al. Interplay of cytokine polymorphisms and bacterial vaginosis in the etiology of preterm delivery. J Reprod Immunol. 2010;87:82–89. [PMC free article] [PubMed]
175. Lamont RF, Sobel JD, Akins RA, et al. The vaginal microbiome: new information about genital tract flora using molecular based techniques. BJOG. 2011;118:533–549. [PMC free article] [PubMed]
176. Donders G, Bellen G, Rezeberga D. Aerobic vaginitis in pregnancy. BJOG. 2011 Jun 14; [Epub ahead of print] [PubMed]